Antibody-Mediated Neutralization of uPA Proteolytic Function Reduces Disease Progression in Mouse Arthritis Models.

Genetic absence of the urokinase-type plasminogen activator (uPA) reduces arthritis progression in the collagen-induced arthritis (CIA) mouse model to an extent just shy of disease abrogation, but this remarkable observation has not been translated into therapeutic intervention. Our aim was to test the potential in mice of an Ab that blocks the proteolytic capacity of uPA in the CIA model and the delayed-type hypersensitivity arthritis model. A second aim was to determine the cellular origins of uPA and the uPA receptor (uPAR) in joint tissue from patients with rheumatoid arthritis. A mAb that neutralizes mouse uPA significantly reduced arthritis progression in the CIA and delayed-type hypersensitivity arthritis models. In the CIA model, the impact of anti-uPA treatment was on par with the effect of blocking TNF-α by etanercept. A pharmacokinetics evaluation of the therapeutic Ab revealed target-mediated drug disposition consistent with a high turnover of endogenous uPA. The cellular expression patterns of uPA and uPAR were characterized by double immunofluorescence in the inflamed synovium from patients with rheumatoid arthritis and compared with synovium from healthy donors. The arthritic synovium showed expression of uPA and uPAR in neutrophils, macrophages, and a fraction of endothelial cells, whereas there was little or no expression in synovium from healthy donors. The data from animal models and human material provide preclinical proof-of-principle that validates uPA as a novel therapeutic target in rheumatic diseases.

A novel knee prosthesis model of implant-related osteomyelitis in rats.

BACKGROUND AND PURPOSE: There have been numerous reports of animal models of osteomyelitis. Very few of these have been prosthesis models that imitate human conditions. We have developed a new rat model of implant-related osteomyelitis that mimics human osteomyelitis, to investigate the pathology of infection after orthopedic implant surgery. METHODS: 2 wild-type strains of Staphylococcus aureus, MN8 and UAMS-1, and their corresponding mutants that are unable to produce poly-N-acetyl glucosamine (PNAG) (ica::tet) were injected into the medullary canals of the femur and tibia at 3 different doses: 10(2), 10(3), and > 10(4) CFU/rat. We measured clinical signs, inflammatory markers, radiographic signs, histopathology, and bacteriology in the infected animals. RESULTS: An inoculum of at least 10(4) cfu of either wild-type bacterial strain resulted in histological, bacteriological, and radiographic signs of osteomyelitis with loosening of the prosthesis. An inoculum of 10(3) CFU gave signs of osteomyelitis but the prosthesis remained in situ. Bacterial inocula of 10(2) cfu gave no signs of osteolysis. INTERPRETATION: We have established a new knee prosthesis model that is suitable for reliable induction of experimental implant-associated osteomyelitis with the prosthesis in situ, using a small inoculum of S. aureus. At a dose of 10(3) CFU/rat, bacteria unable to produce PNAG (ica::tet) had only minor defects in their virulence.

Association between IL-6 production in synovial explants from rheumatoid arthritis patients and clinical and imaging response to biologic treatment: A pilot study.

INTRODUCTION: The need for biomarkers which can predict disease course and treatment response in rheumatoid arthritis (RA) is evident. We explored whether clinical and imaging responses to biologic disease modifying anti-rheumatic drug treatment (bDMARD) were associated with the individual's mediator production in explants obtained at baseline. METHODS: RA Patients were evaluated by disease activity score 28 joint C-reactive protein (DAS 28-)), colour Doppler ultrasound (CDUS) and 3 Tesla RA magnetic resonance imaging scores (RAMRIS). Explants were established from synovectomies from a needle arthroscopic procedure prior to initiation of bDMARD. Explants were incubated with the bDMARD in question, and the productions of interleukin-6 (IL-6), monocyte chemo-attractive protein-1 (MCP-1) and macrophage inflammatory protein-1-beta (MIP-1b) were measured by multiplex immunoassays. The changes in clinical and imaging variables following a minimum of 3 months bDMARD treatment were compared to the baseline explant results. Mixed models and Spearman's rank correlations were performed. P-values below 0.05 were considered statistically significant. RESULTS: 16 patients were included. IL-6 production in bDMARD-treated explants was significantly higher among clinical non-responders compared to responders (P = 0.04), and a lack of suppression of IL-6 by the bDMARDS correlated to a high DAS-28 (ρ = 0.57, P = 0.03), CDUS (ρ = 0.53, P = 0.04) and bone marrow oedema (ρ = 0.56, P = 0.03) at follow-up. No clinical association was found with explant MCP-1 production. MIP-1b could not be assessed due to a large number of samples below the detection limit. CONCLUSIONS: Synovial explants appear to deliver a disease-relevant output testing which when carried out in advance of bDMARD treatment can potentially pave the road for a more patient tailored treatment approach with better treatment effects.

Active and Passive Immunization Against Staphylococcus aureus Periprosthetic Osteomyelitis in Rats.

BACKGROUND/AIM: Staphylococcus aureus infection associated with orthopedic implants cannot always be controlled. We used a knee prosthesis model with implant-related osteomyelitis in rats to explore induction of an effective immune response with active and passive immunization. MATERIALS AND METHODS: Fifty-two Sprague-Dawley rats were divided into active (N=28) and passive immunization groups (N=24). A bacterial inoculum of 103 S. aureus MN8 was injected into the tibia and the femur marrow before insertion of a non-constrained knee prosthesis in each rat. The active-immunization group received a synthetic oligosaccharide of polysaccharide poly-N-acetylglucosamine (PNAG), 9G1cNH2 and the passive-immunization group received immunization with immunoglobulin from rabbits infected with S. aureus. RESULTS/CONCLUSION: Active immunization against PNAG significantly reduced the consequences of osteomyelitis infection from PNAG-producing intercellular adhesion (ica+) but not ica- S. aureus. Passive immunization resulted in better clinical assessments in animals challenged with either ica+ or ica- S. aureus, suggesting a lack of specificity in this antiserum.

[Dissection is still important when learning anatomy]. / Dissektionsundervisning er fortsat vigtig ved indlæring af anatomi.

Dissection and prosection require a donation programme of cadavers for education and research. The importance of maintaining the donation programme and the significance of dissection as a teaching method when learning anatomic structures and obtaining surgical skills are evaluated.

[Acute infections of the hand]. / Håndens akutte infektioner.

Hand infections can result in significant morbidity if not appropriately diagnosed and treated. Host factors, location and circumstances of the infection are important guides to initial treatment strategies. Many hand infections improve with early splinting, elevation and appropriate antibiotics based on bacterial culture. The basic principles for deep infections are bridement of necrotic and infected tissue and healing by second area intension and antibiotics. Hand therapy is important.